Staging is typically divided into regional lymph nodes, especially axillary nodes, and distant or systemic staging of sites beyond regional lymph nodes. Almost all patients with invasive breast cancer will undergo axillary nodal staging since the presence or absence of axillary lymph nodes is an important consideration for further treatment after surgery [16]. The traditional approach to axillary nodal staging was the axillary nodal dissection, where axillary contents were removed and examined; however, the morbidity of this process, including a significant incidence of lymphedema, led to the search for a less morbid but equally accurate approach [16]. This consideration motivated SLN mapping methods, designed to identify and sample the node(s) that are the first draining nodes, that is, “sentinels” in the axillary drainage basin for the breast lesion. SLN biopsy is a shorter surgical procedure than full axillary nodal dissection with much less morbidity [16]. If sentinel nodes are negative, then the chance of “downstream” nodal metastases is quite small, and the patient can be spared the full dissection. If the sentinel node shows evidence of metastasis, then an axillary dissection may be needed to determine the extent of axillary spread. SLN biopsy has been shown to be highly accurate compared to axillary dissection [47–49] and has emerged as the standard of care for axillary nodal sampling in patients with clinically negative axillae [50]. SLN biopsy has been thoroughly tested in large clinical trials and shown to be safe and accurate, with comparable relapse and survival compared to axillary nodal dissection [51, 52].

Radionuclide methods play a key role in SLN biopsy. Typically, for SLN mapping, a colloidal radiopharmaceutical (^99mTc-sulfur colloid in the USA; albumin or antimony nanocolloid in Europe) is injected, and sentinel nodes are identified through imaging (lymphoscintigraphy, Fig. 12.2), gamma probes, or both [53]. Other, more specific agents have been developed and are undergoing testing [54]. Some centers use both radiocolloid and visible blue dye to guide SLN sampling, while some centers use one of the methods without the other [16].

Early studies used perilesional injection of radiotracer or blue dye with the goal of mapping lymphatic drainage pathways arising from the tumor site [55]. Subsequent studies showed that intradermal injection over the lesion site or peri-areolar injection identified the same axillary SLN found by perilesional injection [56] and provided accuracy for axillary SLN sampling [57]. However, most studies done using radiocolloid and lymphoscintigraphy suggest that only perilesional injection depicts extra-axillary drainage, especially to internal mammary (IM) nodes [55]. Studies have shown that approximately 15–20% of non-upper outer quadrant (UOQ) lesions drain to IM lymph nodes after perilesional injection [58]; however, this rate is much smaller for other injection methods [55]. The importance of sampling IM nodes is a point of considerable debate [59]. Studies using SLN mapping and lymphoscintigraphy to sample IM lymph have demonstrated the feasibility of this approach [60–62]; however, the overall percentage of positive IM nodes is on the order of 5% or less, and it is rare to have IM lymph node metastasis in the absence of axillary nodal metastases [63]. As a result, most practices in the USA do not routinely sample IM nodes. Yao et al. [64] found that patients with positive axillary nodes and IM nodal drainage, even in the absence of IM nodal sampling, were significantly more likely to relapse and die of breast cancer than those without drainage. Another study found a higher rate of nodal relapse outside the axilla, versus in the axilla, after sentinel node biopsy [65]. Such studies prompt careful consideration of the approach to SLN mapping in breast cancer and the potential benefit of perilesional injection and lymphoscintigraphy in selected patients to identify extra-axillary drainage.

There has been considerable interest in noninvasive imaging to detect axillary nodal spread in breast cancer and avoid the need for invasive biopsy. This has been best studied for [¹⁸F]FDG-PET (reviewed in Crippa et al. [66]). Early studies showed high sensitivity (also reviewed in Eubank et al. [67]), suggesting feasibility of [¹⁸F]FDG-PET as a noninvasive method for axillary staging and potential substitute for axillary nodal dissection. However, more recent studies with larger fraction of smaller primary cancers, comparable to the size found in screened populations, demonstrated sensitivities as low as 20–30% for axillary nodal metastases (reviewed in Rosen et al. [43]). In a prospective multicenter trial representing one of the largest patient cohorts to date [68], [¹⁸F]­FDG-PET was performed in 360 women with newly diagnosed invasive breast cancer, and the results were interpreted blindly by three experienced readers and compared to pathologic analysis of axillary nodes. Overall, [¹⁸F]FDG-PET was 61% sensitive and 80% specific for axillary metastases, with a positive predictive value of 62% and a negative predictive value of 79%. Further studies comparing [¹⁸F]­FDG-PET to SLN biopsy support SLN biopsy for early-stage disease and confirmed limited sensitivity of [¹⁸F]­FDG-PET for axillary nodal metastases in this clinical setting compared to SLN biopsy (as low as 20–40%), particularly in small (ranging from 1 to 15 mm) and isolated lesions [43 69]. These results indicate the limitation of [¹⁸F]­FDG-PET in detection of micrometastases and small tumor-infiltrated axillary lymph nodes and indicate that [¹⁸F]­FDG-PET is not sufficiently sensitive to replace SLN biopsy in patients with early-stage breast cancer.

Although [¹⁸F]FDG-PET has limited sensitivity for axillary nodal metastases in early breast cancer, it has high specificity; most studies demonstrate specificities in the range of 93–100% (reviewed in Rosen et al. and Eubank et al. [43 70]). This high specificity has led some to suggest that [¹⁸F]­FDG-PET may be useful in patient at higher risk for axillary nodal spread, including those with palpable nodes, avoiding the need for SLN biopsy in patients shown to have definitive evidence of axillary spread [70–75]. In such patients, a positive [¹⁸F]FDG-PET would direct the patient to full axillary dissection, while a negative [¹⁸F]FDG study would be followed by SLN biopsy to rule out small-volume disease missed by PET. In current practice, however, this role has largely been taken over by axillary ultrasound, which can also be used to direct nodal sampling for confirmation of nodal metastases [76, 77].

[¹⁸F]FDG-PET has performed well in regional nodal staging in patients with more advanced cancers, including patients with palpable axillary disease, plexopathy, or symptomatic metastases [78]. This is an important use of [¹⁸F]­FDG-PET/CT for breast cancer and can be helpful for directing treatments such as regional radiotherapy [79].

[¹⁸F]FDG-PET may be helpful in assessing breast cancer spread to regional nodal sites outside of the axilla, especially the IM chain (Fig. 12.3). [¹⁸F]FDG uptake in IM nodes has been reported in some studies of nodal staging in patients with more advanced disease, showing IM nodal uptake as high as 25% [80, 81]. Some reports suggest that IM [¹⁸F]­FDG uptake predicts treatment failure patterns of disease consistent with IM nodal involvement and progression [81]. Tran et al. showed that the likelihood of extra-axillary lymph node finding on [¹⁸F]FDG-PET was dependent upon the position of tumor (medial vs. lateral), and the presence of extra-axillary nodal uptake on [¹⁸F]FDG-PET combined with medial tumor location indicated a high risk of subsequent disease progression [82]. An early study by Jones and colleagues showed the feasibility of detecting IM nodal metastases in early-stage patients using [¹⁸F]FDG-PET [83], although more data are required to further validate these results.

For patients with early-stage breast cancer and without ­evidence of regional nodal spread (stage I or low end of stage II), systemic staging is not recommended unless there are symptoms [84] since the chance of distant metastases is low and the chance of false-positive findings in staging studies is considerably higher than the chance of true positive findings [85, 86]. For recurrent breast cancer or breast cancer with known metastases, systemic staging is recommended [84]. For locally advanced breast cancer (LABC), especially for patients with advanced axillary nodal disease, the risk of ­systemic metastases is high enough that systemic staging is recommended as part of the initial evaluation [87].

Important areas of more distant spread for breast cancer include nodal beds outside the axillary and IM chain, for example, in the mediastinum, the lungs, the liver, and bones [88]. In patients with symptoms, other sites, for example, the brain, may be investigated. While anatomic imaging (largely using CT of the chest, abdomen, and possibly pelvis) plays a large role in systemic staging, radionuclide methods, especially PET and bone scintigraphy, also play key roles.

Between 30 and 85% of patients with metastatic breast cancer (MBC) have bone metastases during the course of disease, and bone is the first site of metastasis for 26–50% of patients with metastatic breast carcinoma [89, 90]. Bone metastases in breast cancer can be both osteoblastic and osteolytic. Breast cancer preferentially metastasizes to the spine and pelvis, followed by ribs, skull, and femur [90]. Bone scanning is the most commonly used method for breast cancer bone metastasis staging [90] (Fig. 12.4). The reported sensitivity ranges from 62 to 100% and specificity ranges from 78 to 100% [90, 91]. False positives can be caused by trauma, degenerative changes, and other benign conditions, while false negatives can occur in presence of predominantly osteolytic metastases, low bone turnover, or in avascular regions (such as necrosis) [90]. Single-photon emission computed tomography (SPECT) may improve the performance of bone scanning for bone metastasis staging [92]. SPECT is particularly helpful to characterize solitary lesions in the spine and/or to differentiate bone metastases from degenerative lesions. Salvelli et al. reported the sensitivity and specificity of SPECT to be over 90% [92].

Some studies shown that fluoride (¹⁸F⁻) PET (Fig. 12.5) is superior to bone scan and SPECT in detecting bone metastases and differentiating malignant from benign lesions [93–95]. The mechanism of localization of fluoride in bone and uptake in bone metastases is similar to diphosphonates in that both are deposited in newly mineralizing bone accompanying osteoblastic activity [96]. ¹⁸F⁻ has practical advantages over ^99mTc-labeled bone scan agents that include faster clearance and higher contrast [96]. ¹⁸F⁻ PET/CT may be particularly helpful in relating biochemical changes in bone detected by PET to anatomic abnormalities seen on CT, helping with specificity [93, 94]. Sensitivity may also improve using fluoride PET compared to bone scan. Schirrmeister and colleagues found more metastatic lesions on ¹⁸F⁻ PET compared to bone scan with additional SPECT, impacting clinical management in 12% of patients [93]. Although recent studies have successfully shown ¹⁸F⁻ PET to have higher diagnostic accuracy in assessment of bone metastases, long-standing familiarity with bone scan, concerns regarding cost, and a lack of data on the clinical impact of improved diagnostic accuracy of ¹⁸F⁻ PET compared to bone scan have somewhat limited the use of ¹⁸F⁻ PET, although its use can be expected to increase with increased experience and data.

[¹⁸F]FDG-PET and PET/CT have been increasingly used in systemic staging for recurrent or MBC (Fig. 12.6). The reported sensitivities and specificities of [¹⁸F]FDG-PET for detection of distant metastases are 80–100% and 50–97%, respectively (summarized in Eubank et al. [97]). In an early study of [¹⁸F]FDG-PET for breast cancer systemic staging, Moon and colleagues performed [¹⁸F]FDG-PET in 57 patients suspected of having recurrent or MBC and demonstrated that [¹⁸F]FDG-PET was 93% sensitive and 79% specific [98]. [¹⁸F]FDG-PET is also reported to be more sensitive compare to conventional imaging modalities; Mahner and colleagues showed that [¹⁸F]FDG-PET was 87% sensitive and 83% specific while combined conventional imaging modalities were 43% sensitive and 98% specific [99]. The addition of CT for [¹⁸F]FDG-PET/CT improve performance further [100] and is now widely used for systemic breast cancer staging in patients with advanced disease [101].

The additional sensitivity of [¹⁸F]FDG-PET/CT for regional nodes and distant disease may be particularly important in staging for locally advanced breast cancer (LABC). LABC, including primary tumor larger than 5 cm, skin or chest wall involvement, fixed axillary nodes, positive supraclavicular/infraclavicular/IM nodes and inflammatory cancer, has a poor prognosis because of the high incidence of distant metastases during follow-up [87, 102]. Currently, the standard approach is neoadjuvant chemotherapy followed by surgery with axillary nodal dissection and radiation with the intent of cure. However, some patients with apparent LABC may have occult distant metastases, in which case aggressive therapies with curative intent may not be indicated. Thus, detecting distant metastases in the patients with LABC is crucial for determination of treatment. There is evidence to support the utility of [¹⁸F]FDG-PET in LABC at diagnosis. Recent studies have shown that [¹⁸F]FDG-PET and PET/CT will detect additional sites of regional nodal spread and/or distant metastases not found by standard imaging in up to 25% of patients (Table 12.3) [80, 81, 99, 103–106]. The rate of detection is especially high in inflammatory breast cancer [106]. Thus, [¹⁸F]FDG-PET/CT may be increasingly used as part of the initial evaluation of LABC.